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Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle.

Lewis P, Sheehan D, Soares R, Varela Coelho A, O'Halloran KD - Front Physiol (2015)

Bottom Line: There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation.We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis.Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, School of Medicine, University College Cork Cork, Ireland.

ABSTRACT
Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid-a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease.

No MeSH data available.


Related in: MedlinePlus

Representative image of 2D-PAGE sternohyoid muscle protein profile after coomassie staining of proteins. A molecular mass marker ranging from 14 to 116 kDa is shown for size reference and isoelectric point is indicated along the range pH 10-3. Spot numbers match those presented in Table 2.
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Figure 5: Representative image of 2D-PAGE sternohyoid muscle protein profile after coomassie staining of proteins. A molecular mass marker ranging from 14 to 116 kDa is shown for size reference and isoelectric point is indicated along the range pH 10-3. Spot numbers match those presented in Table 2.

Mentions: In the sternohyoid, 498, 264, and 996 resolved spots were matched in FTSC-, IAF-labeled and coomassie-stained separations respectively. A significant relative volume difference was observed in 87 FTSC, 51 IAF, and 156 coomassie spots comparing control and CH groups (p < 0.05). Proteins were selected for mass spectrometry analysis based on separation, resolution, abundance, and overlap in fluorescence-stain and muscle separations. Protein smears and gel defects were excluded. Results for protein remodeling are presented in Table 2 with proteins grouped according to cellular location and/or function. Selected spots can be visualized on the representative coomassie stained gel shown in Figure 5. A change in FTSC and IAF fluorescence intensity signal independent of, or differential to, coomassie signal is indicative of protein redox remodeling.


Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle.

Lewis P, Sheehan D, Soares R, Varela Coelho A, O'Halloran KD - Front Physiol (2015)

Representative image of 2D-PAGE sternohyoid muscle protein profile after coomassie staining of proteins. A molecular mass marker ranging from 14 to 116 kDa is shown for size reference and isoelectric point is indicated along the range pH 10-3. Spot numbers match those presented in Table 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403307&req=5

Figure 5: Representative image of 2D-PAGE sternohyoid muscle protein profile after coomassie staining of proteins. A molecular mass marker ranging from 14 to 116 kDa is shown for size reference and isoelectric point is indicated along the range pH 10-3. Spot numbers match those presented in Table 2.
Mentions: In the sternohyoid, 498, 264, and 996 resolved spots were matched in FTSC-, IAF-labeled and coomassie-stained separations respectively. A significant relative volume difference was observed in 87 FTSC, 51 IAF, and 156 coomassie spots comparing control and CH groups (p < 0.05). Proteins were selected for mass spectrometry analysis based on separation, resolution, abundance, and overlap in fluorescence-stain and muscle separations. Protein smears and gel defects were excluded. Results for protein remodeling are presented in Table 2 with proteins grouped according to cellular location and/or function. Selected spots can be visualized on the representative coomassie stained gel shown in Figure 5. A change in FTSC and IAF fluorescence intensity signal independent of, or differential to, coomassie signal is indicative of protein redox remodeling.

Bottom Line: There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation.We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis.Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, School of Medicine, University College Cork Cork, Ireland.

ABSTRACT
Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid-a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease.

No MeSH data available.


Related in: MedlinePlus